Heart failure (HF) is a disabling condition involving complex vascular, neurohormonal and immune systems' interactions. Osteoprotegerin (OPG), a bone-regulatory cytokine, has been suggested to play a key role in skeletal, vascular, and immune biology, with elevated levels observed in both experimental and clinical HF. In the present study we aimed to identify clinical OPG correlates and investigated whether elevated OPG, as a marker of HF vascular and immune activation, may interact with N-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of HF neurohormonal activation, thus synergistically increasing HF risk. We used a case-cohort study, nested within the European Prospective Investigation into Cancer and Nutrition-Potsdam, comprising 2647 participants including 252 incident HF cases identified during a mean follow-up of 8.2 ± 1.6 years. In both men and women significant positive associations were observed between OPG and age, smoking, prevalent diabetes, C-reactive protein, sex hormone-binding globulin, and additionally prevalent coronary heart disease and uric acid in men only. In women, OPG was furthermore positively related to hypertension and fetuin-A. After multivariable adjustment each doubling of OPG was associated with a 3.01-fold increased HF risk (95 % CI 1.49-6.06) in men. A significant interaction was observed between OPG and NT-proBNP. In men, a combination of high levels of both OPG and NT-proBNP, compared to a combination of low levels, was associated with an approximately fivefold increased HF risk. In women, no associations were observed. These findings suggest that, in men, the activation of different immune, neurohormonal, and vascular pathophysiological pathways may confer increased HF risk.
Keywords: Additive interaction; Cytokine; Determinants; Myocardial failure.